Halogenation of activated carbon atoms is a highly useful reaction for the synthesis of natural products and pharmaceutically important compounds. Aromatic compounds are examples of compounds with activated carbon atoms. Aryl fluorides and chlorides are found in many natural products and pharmaceutical compounds. Aryl bromides and iodides are important building blocks in organic syntheses because of their utility in carbon-carbon bond forming reactions. For example, aryl bromides and iodides are precursors to numerous organometallic species that are used in organic synthesis. Organometallic species and aryl bromides and iodides or benzyl bromides or iodides are useful in cross coupling reactions, in particular, transition metal catalyzed cross coupling reactions that can furnish complex molecules under mild reaction conditions.
Classical reagents for the direct introduction of halogen atoms at an activated carbon atom are bromine, chlorine and iodine, for example. These reagents have a number of drawbacks including toxicity, high reactivity, corrosiveness, nonselectivity particularly in molecules with complex and sensitive functionality, as well as the fact that only half of the halogen in the reagent is consumed. In addition, the reaction product mixtures arising from these reagents can lead to high levels of toxic and corrosive waste, as well as purification difficulties. Halogenation of aromatic compounds is disclosed in Prakash, G. K. S., Mathew, T., Hoole, D., Esteves, P. M. J. Am. Chem. Soc. 2004, 126, 15770; Tanemura, K., Suzuki, T., Nishida, Y.; Satsumabayashi, K., Horaguchi, T. Chem. Lett. 2003, 32, 932; and Zanka, A., Kubota, A. Synlett 1999, 12, 1984.
In terms of ease of handling, haloimides are ideal halogenating reagents. For example, NBS, NIS, NCS and NFSI are solids that are non-corrosive, nonhydroscopic, and mild reagents that are easily handled under standard conditions. Previous attempts to employ these reagents for aromatic halogenation, however, have usually required severe reaction conditions to activate or enhance the halogenating ability of these compounds. For example, previous attempts employed highly acidic solutions, large amounts of catalyst and/or high temperatures.
It is desirable to have new methods for the halogenation of activated carbon atoms which are mild and tolerate complex functionality, particularly in the synthesis of complex organic molecules such as natural and pharmaceutical products.